Featured Research

from universities, journals, and other organizations

Duality of longevity drug explained

Date:

March 29, 2012

Source:

Perelman School of Medicine at the University of Pennsylvania

Summary:

Scientists have now explained how rapamycin, a drug that extends mouse lifespan, also causes insulin resistance. The researchers showed in an animal model that they could, in principle, separate the effects, which depend on inhibiting two protein complexes, mTORC1 and mTORC2, respectively. The study suggests that molecules that specifically inhibit mTORC1 may combat age-related diseases without the insulin-resistance side effect, which can predispose people to diabetes.

Share This

A Penn- and MIT-led team explained how rapamycin, a drug that extends mouse lifespan, also causes insulin resistance. The researchers showed in an animal model that they could, in principle, separate the effects, which depend on inhibiting two protein complexes, mTORC1 and mTORC2, respectively.

Related Articles

The study suggests that molecules that specifically inhibit mTORC1 may combat age-related diseases without the insulin-resistance side effect, which can predispose people to diabetes.

Senior author Joseph A. Baur, PhD, assistant professor of Physiology, Perelman School of Medicine, University of Pennsylvania, and colleagues at the Whitehead Institute for Biomedical Research and Broad Institute, Massachusetts Institute of Technology, in Cambridge, MA, describe their work in this week's issue of Science. Baur is also a member of Penn's Institute for Diabetes, Obesity, and Metabolism.

"The hope is that in the future, we will be able to develop molecules that target mTORC1 specifically, separating out the beneficial effects of rapamycin on aging and disease, and leaving behind the insulin-resistance side effect," says Baur.

"Our results demonstrate that reduced mTORC1 signaling is sufficient to extend lifespan and mTORC2 signaling has profound effects on metabolism," says co-first author Lan Ye, PhD, postdoctoral fellow in the Baur lab. "Our findings indicate that mTORC2 may be an important player in the pathogenesis of type 2 diabetes and metabolic syndrome."

One Compound, Many Effects Rapamycin extends the lifespan of yeast, flies, and mice and is also an immunosuppressant drug for organ transplants and an anti-cancer drug. It was first discovered as a byproduct of Streptomycin hygroscopicus, a bacterium found in a soil sample from Easter Island, an island also known as Rapa Nui, hence the name. Rapamycin was originally developed as an antifungal agent, but that use was abandoned when it was discovered to have immunosuppressive properties.

The mTOR complexes, for mammalian (or mechanistic) target of rapamycin, are proteins that regulate cell growth, movement, and survival, as well as protein synthesis and transcription. Specifically, there are two mTOR complexes and one mTOR protein. The mTOR protein is the core of both complexes (mTORC1 and mTORC2), which behave differently based on their associated proteins. One or both of the mTOR complexes can be inappropriately activated in certain cancers, and dual-specific inhibitors are being developed as chemotherapeutic agents.

Several theories have been put forward by researchers to explain the observations that patients receiving rapamycin are more prone to developing glucose intolerance, which can lead to diabetes. Chronic treatment with rapamycin impairs glucose metabolism and the correct functioning of insulin in mice, despite extending lifespan. The research team demonstrated that rapamycin disrupts mTORC2 in the mice, and that mTORC2 is required for the insulin-mediated suppression of glucose metabolism in the liver.

On the other hand, they also demonstrated that decreasing mTORC1 signaling was sufficient to extend lifespan independently from changes in glucose metabolism. They used a mouse strain in which mTORC1 activity was decreased and saw that lifespan was extended by 14 percent, yet the animals had normal glucose metabolism and insulin sensitivity.

"Besides developing more specific inhibitors for mTORC1, we remain very interested in understanding why mTORC1 inhibition extends life in the first place," explains Baur. "We're currently looking at the interactions between mTORC1 and other pathways that influence longevity, as well as its effects on things like free radical generation and protein quality control."

The MIT colleagues on the Science paper are co-first author Dudley W. Lamming, PhD, Whitehead Institute, and co-senior author David M. Sabatini, MD, PhD, member of Whitehead Institute, Howard Hughes Medical Institute investigator, and professor of biology at MIT. This study was funded by grants from the American Federation for Aging Research, the National Cancer Institute, and the Bingham Trust, through Penn's Institute on Aging.

Perelman School of Medicine at the University of Pennsylvania. "Duality of longevity drug explained." ScienceDaily. ScienceDaily, 29 March 2012. <www.sciencedaily.com/releases/2012/03/120329141529.htm>.

Perelman School of Medicine at the University of Pennsylvania. (2012, March 29). Duality of longevity drug explained. ScienceDaily. Retrieved March 3, 2015 from www.sciencedaily.com/releases/2012/03/120329141529.htm

Perelman School of Medicine at the University of Pennsylvania. "Duality of longevity drug explained." ScienceDaily. www.sciencedaily.com/releases/2012/03/120329141529.htm (accessed March 3, 2015).

More From ScienceDaily

More Health & Medicine News

Featured Research

Mar. 3, 2015 — Why do people shake hands? A new study suggests one of the reasons for this ancient custom may be to check out each other's odors. Even if we are not consciously aware of this, handshaking may ... full story

Mar. 3, 2015 — It appears that stress markers in unemployed people can be found, independent of smoking, alcohol consumption and overweight/obesity. Results from a study suggest that long-term unemployment may be ... full story

Mar. 3, 2015 — Doctors write millions of prescriptions a year for drugs to calm the behavior of people with Alzheimer’s disease and other types of dementia. But non-drug approaches actually work better, and carry ... full story

Mar. 3, 2015 — Briefly counseling college students on the dangers of binge drinking is effective in lowering heavy drinking levels among many students, but only temporarily. Three out of four will be right back ... full story

Mar. 3, 2015 — Body mass index in healthy adolescents has a statistically significant association with both systolic blood pressures and diastolic blood pressures, research shows, and it highlights the significance ... full story

Mar. 3, 2015 — Loneliness brought about by the death of a spouse can trigger a wider network of depression-like symptoms, a study has found, but authors suggest that doctors are often too quick to attribute these ... full story

Mar. 3, 2015 — Family Based Interpersonal Psychotherapy (FB-IPT) is more effective in treating preadolescent children with depression compared to child-centered therapy (CCT), a recent study has found. ... full story

Mar. 3, 2015 — Two of the four known groups of human AIDS viruses (HIV-1 groups O and P) have originated in western lowland gorillas, according to new research. The scientists conducted a comprehensive survey of ... full story

Mar. 3, 2015 — Scientists have succeeded in producing cartilage formed from embryonic stem cells that could in future be used to treat the painful joint condition osteoarthritis. With their huge capacity to ... full story

Featured Videos

Mom Triumphs Over Tragedy, Helps Other Families

AP (Mar. 3, 2015) — After her son, Dax, died from a rare form of leukemia, Julie Locke decided to give back to the doctors at St. Jude Children&apos;s Research Hospital who tried to save his life. She raised $1.6M to help other patients and their families. (March 3)
Video provided by AP

Woman Convicted of Poisoning Son

AP (Mar. 3, 2015) — A woman who blogged for years about her son&apos;s constant health woes was convicted Monday of poisoning him to death by force-feeding heavy concentrations of sodium through his stomach tube. (March 3)
Video provided by AP

More Coverage

Mar. 29, 2012 — The drug rapamycin extends lifespan in lab animals, yet it's linked to two hallmarks of diabetes. By teasing apart its activity, researchers have determined that inhibiting only the protein ... read more

Related Stories

Feb. 9, 2015 — Rapamycin extends lifespan in mice up to 30 percent, making it of major interest to scientists studying aging. But long term use of rapamycin, approved for use in several disease indications, has ... full story

Oct. 28, 2014 — A major contributor to Huntington’s disease, a devastating progressive neurological condition that produces involuntary movements, emotional disturbance and cognitive impairment, has been uncovered ... full story

Aug. 11, 2014 — The protein mTOR is a central controller of growth and metabolism. Deregulation of mTOR signaling increases the risk of developing metabolic diseases such as diabetes, obesity and cancer. Researchers ... full story

ScienceDaily features breaking news and videos about the latest discoveries in health, technology, the environment, and more -- from major news services and leading universities, scientific journals, and research organizations.